Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

Darren Boehning; Randen L. Patterson; Leela Sedaghat; Natalia O. Glebova; Tomohiro Kurosaki; Solomon H. Snyder

doi:10.1038/ncb1063

Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

Darren Boehning, Randen L. Patterson, Leela Sedaghat, Natalia O. Glebova, Tomohiro Kurosaki, Solomon H. Snyder

Research output: Contribution to journal › Article › peer-review

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Abstract

Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InSp₃R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP₃R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InSP₃R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP₃R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP₃R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

Original language	English (US)
Pages (from-to)	1051-1061
Number of pages	11
Journal	Nature Cell Biology
Volume	5
Issue number	12
DOIs	https://doi.org/10.1038/ncb1063
State	Published - Dec 2003
Externally published	Yes

All Science Journal Classification (ASJC) codes

Cell Biology

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10.1038/ncb1063

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title = "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis",

abstract = "Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InSp3R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP3R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InSP3R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP3R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP3R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.",

author = "Darren Boehning and Patterson, {Randen L.} and Leela Sedaghat and Glebova, {Natalia O.} and Tomohiro Kurosaki and Snyder, {Solomon H.}",

note = "Funding Information: The authors thank D.B. Murphy for valuable comments and FRET instrumentation. We also thank S.K. Joseph for an initial supply of anti-InsP3R-I antibody and InsP3R expression constructs. We appreciate the support and useful discussion of D. Van Rossum, R.E. Rothe and P. Stankovic. This work was supported by USPHS grants MH-18501 and DA-000266 and Research Scientist Award DA-00074 (SHS), and National Research Service Awards NS-043850 (D.B.) and NH65090 (R.L.P.).",

year = "2003",

month = dec,

doi = "10.1038/ncb1063",

language = "English (US)",

volume = "5",

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AU - Boehning, Darren

AU - Patterson, Randen L.

AU - Sedaghat, Leela

AU - Glebova, Natalia O.

AU - Kurosaki, Tomohiro

AU - Snyder, Solomon H.

N1 - Funding Information: The authors thank D.B. Murphy for valuable comments and FRET instrumentation. We also thank S.K. Joseph for an initial supply of anti-InsP3R-I antibody and InsP3R expression constructs. We appreciate the support and useful discussion of D. Van Rossum, R.E. Rothe and P. Stankovic. This work was supported by USPHS grants MH-18501 and DA-000266 and Research Scientist Award DA-00074 (SHS), and National Research Service Awards NS-043850 (D.B.) and NH65090 (R.L.P.).

PY - 2003/12

Y1 - 2003/12

N2 - Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InSp3R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP3R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InSP3R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP3R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP3R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

AB - Mitochondrial cytochrome c release and inositol (1,4,5) trisphosphate receptor (InSp3R)-mediated calcium release from the endoplasmic reticulum mediate apoptosis in response to specific stimuli. Here we show that cytochrome c binds to the InsP3R during apoptosis. Addition of 1 nM cytochrome c blocks calcium-dependent inhibition of InSP3R function. Early in apoptosis, cytochrome c translocates to the endoplasmic reticulum where it selectively binds InsP3R, resulting in sustained, oscillatory cytosolic calcium increases. These calcium events are linked to the coordinate release of cytochrome c from all mitochondria. Our findings identify a feed-forward mechanism whereby early cytochrome c release increases InsP3R function, resulting in augmented cytochrome c release that amplifies the apoptotic signal.

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Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

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